There has been a long-standing interest in gaining further insights into rare tumors whose etiology is poorly understood. At present, this project is focusing the majority of efforts on four tumors--nasopharyngeal cancer, biliary cancer, liver cancer, and multiple myeloma.[unreadable] [unreadable] Nasopharyngeal cancer (NPC) has a very distinct geographic and ethnic distribution, occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasian populations. While infection with the Epstein Barr virus (EBV) is believed to be necessary for development of the cancer, other factors, both genetic and exogenous, are also thought to be important. To investigate genetic, dietary, occupational, and behavioral factors related to the etiology of NPC, a case-control study was conducted in Taiwan. To date, our results suggest an association between risk and specific variants of the enzyme CYP2E1 and several DNA repair genes, specific patterns of HLA and KIR genes, and long-term cigarette smoking. High intakes of nitrosamines and nitrite during childhood and weaning also were associated with increased risks. Occupational exposures to wood dusts also appeared to affect risk; in contrast, formaldehyde exposure was not a significant risk factor. A large-scale family (linkage) study is ongoing in Taiwan to enable a careful and systematic assessment of genetic and environmental determinants of this cancer. A genome-wide screen conducted within our family study indicated the importance of a specific region of chromosome 14 in the etiology of the disease. Results from our efforts also indicate that unaffected family members from our high-risk families have elevated levels of antibodies against EBV compared to the general population. To evaluate the possibility that these individuals with elevated levels of antibodies against EBV are at increased risk of NPC clinical follow-up of this population is underway.[unreadable] [unreadable] During the last 25 years, the incidence of biliary tract cancer in Shanghai has increased more rapidly than that of any other malignancy. The sharply rising trend suggests a change in the prevalence of risk factors. To elucidate these factors, we conducted a population-based interdisciplinary study of biliary tract cancer. More than 3,000 subjects were enrolled in the study, including over 600 biliary tract cancer patients, 900 gallstone patients, and 1,000 healthy controls randomly selected from the population. A structured questionnaire was used to elicit information on epidemiologic risk factors, including smoking, drinking, diet, medical history, and reproductive factors. The study had a strong biochemical and molecular component with an extensive collection of biological samples, including serum, DNA, urine samples, gallstones, bile, and tissue samples. The extensive collection of biological specimens, the carefully collected high-quality exposure data, and the large size of the study will permit testing of a number of emergent hypotheses related to biliary tract cancer. To date, molecular analyses from tumor tissue collected in the study showed that the prevalence of mutations of several genes, including beta-catenin, p53, p16, and K-ras, varies by anatomic subsite and histology, suggesting that the molecular and causal pathways of biliary tract neoplasms may differ by anatomic subsite and histological subtype. We have also reported that higher risks of biliary tract cancer were associated with a history of gallstones, a family history of gallstones, multiparity (for gallbladder cancer, among women only), obesity, consumption of preserved foods, and a history of cholecystitis or pancreatitis; in contrast, tea drinking was associated with reduced risk among women. Chronic carriers of the hepatitis B virus had a 2-fold risk of bile duct cancer.